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Science2Startup
In the Science2Startup (S2S) symposium that took place on May 3, 2023, Kirill Martemyanov, the Co-founder of EvoDenovo, was one of the ten presenters. He shared new strategies for enhancing the safety of opioid drugs and combating opioid use disorder, based on the innovative discovery of novel drug targets.
Orphan GPCR exhibits anti-opioid activity
Improved understanding of the mammalian μ-opioid receptor (MOR) system is vital for the development of safer opioid analgesics. Here, Wang et al. generate transgenic Caenorhabditis elegans expressing the mammalian MOR (tgMOR) for unbiased genetic discovery of opioid modulators. By engineering mutations in ∼2,500 tgMOR animals, they ultimately identified the orphan receptor, GPR139, as a negative regulator of MOR signalling. GPR139 is coexpressed with MOR in opioid-sensitive brain regions and influences MOR trafficking and signalling properties. GPR139 deletion in mice enhanced opioid-induced inhibition of neuronal firing, increased the analgesic and rewarding effects of morphine and reduced withdrawal.
Countering opioid side effects
Over 45,000 Americans now die annually from opioid overdose, surpassing deaths from car accidents. Opioids cause two-thirds of drug-related deaths globally. To combat this, scientists are developing treatments to prevent opioid side effects like addiction and fatal respiratory depression. In recent research, Wang et al. found that GPR139, an orphan G protein-coupled receptor, regulates opioid receptors and may help reduce these side effects.
An Anti-Opioid System, Courtesy of a Worm Model
A forward genetic screen using the worm Caenorhabditis elegans implicated the G protein–coupled receptor 139 in suppressing signaling by the mu opioid receptor. Further experiments in mouse models suggest that antagonizing this receptor could enhance the analgesic efficacy of medicinal opioids.
Worms lead scientists to a new anti-opioid system
NIH-funded researchers used gene-modified worms to identify a biological system, featuring the gene GPR139, that counteracts opioid effects. This discovery, which was tested in mice, could potentially increase opioid safety and reduce addiction risks. The findings also emphasize the potential of using the simple C. elegans worm for genetic discovery. The research, conducted by scientists at Scripps Research and the University of Kansas, was recently published in Science.
